1. Field of the Invention
The present invention relates to certain sufonamide derivatives that inhibit procollagen C-proteinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
2. Background Information and Related Disclosures
The collagens are integral components of connective tissue. At present nineteen types of collagens have been identified. The interstitial collagen types I, II, and III are the major collagen components of tissue. These collagens are synthesized as procollagen precursor molecules having amino- and carboxy-terminal peptide extensions also known as pro-regions. These pro-regions are typically cleaved upon secretion of the procollagen molecule to give a mature collagen molecule which is capable of association into highly structured collagen fibers, ((see, e.g., Fessler and Fessler, Annu. Rev. Biochem. 47, 129, (1978); Kivirikko et al., Extracellular Matrix Biochemistry (1984) and Kuhn, Structure and Function of Collagen Types (eds. Mayne, R and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla., pp. 1-42 (1987)). It is well established that excessive collagen deposition is associated with a variety of fibrotic diseases such as interstitial pulmonary fibrosis, pericentral fibrosis, Symmers' fibrosis, perimuscular fibrosis, kidney fibrosis, endocardial sclerosis, hepatitis, acute respiratory distress syndrome, arthritis, cystic fibrosis, tendon surgery, corneal scarring, surgical adhesions, scleroderma, chronic allograft rejection, hemodialysis shunt fibrosis, liver fibrosis and restenosis. These diseases are chatacterized by excessive deposits of fibrillar interstitial collagens that are resistant to proteolytic degradation thus leading to the symptoms of fibrosis. Therefore, inhibition of the pathological deposition of these collagens should help in the treatment of these diseases.
Recent studies suggest that C-proteinase is the essential enzyme that catalyzes the cleavage of the C-propeptide of types I, II, and III collagens and is therefore instrumental in the formation of functional collagen fibers ((see, Fertala et al., J. Biol. Chem., 269, 11584, (1994)). It would therefore be desirable to provide procollagen C-proteinase inhibitors and thereby provide a means of combating diseases mediated by excessive deposition of these collagens. The compounds of this invention fulfill this and related needs.